Award details

Perinatal programming of stress response and nociceptive mechanisms and the welfare consequences

Reference	BB/C518957/1
Principal Investigator / Supervisor	Professor John Russell
Co-Investigators / Co-Supervisors	Professor Susan Fleetwood-Walker, Professor Jonathan Seckl
Institution	University of Edinburgh
Department	Biomedical Sciences
Funding type	Research
Value (£)	1,112,286
Status	Completed
Type	Research Grant
Start date	01/01/2006
End date	31/12/2010
Duration	60 months

Abstract

The project brings together experts in the study of behaviour, pain, genetics and welfare in farm animals, and experts in analysing pain and neuroendocrine stress mechanisms in laboratory rodents. The team will investigate the importance of adverse early life experience in `programming¿ exaggerated responses to pain and stress in adulthood in pigs, the mechanisms by which programming is expressed, and whether it can be over-written. Studies on several species, including humans, indicate that programming has wide-ranging deleterious health and quality of life consequences, attributable to re-setting responsiveness of the hypothalamo-pituitary-adrenal (HPA) stress axis and neuronal responsiveness to noxious stimuli in spinal cord. We will use two early life challenges relevant to modern pig-farming, social mixing of pregnant gilts (which is stressful, and as we have recently shown, programmes the offspring¿s HPA axis) and neonatal tail-docking (which is painful). We will study their effects, alone and together, on emotional behaviour, stress responses, and pain sensitivity of the female offspring as juveniles and adult sows. Quality of life methodologies will provide an integrated assessment of the effects of these early life experiences on pig welfare. The behaviour and welfare studies will be complemented by genetic analysis, stress hormone (salivary cortisol) measurement, and post-mortem studies of gene expression (quantitative in situ hybridisation) in the hypothalamus and limbic brain for mRNAs coding proteins proposed to regulate HPA axis and emotional and behavioural responses to stress. The project will provide new information about pain sensitivity after pre-natal stress and tail-docking, evaluating their long term consequences, and analyse expression of key genes involved in processing pain in the primary nociceptive relays in the spinal cord. The CNS gene expression studies will both provide quantitative markers to corroborate the whole animal studies, andindicate potential therapeutic targets for overwriting programming, or prevention by selective breeding. We will also investigate potential genetic markers of susceptibility to adverse programming by analysing the genetic basis of stress reactivity in a commercial pig breeding population, which may point the way to a programme of behavioural genetic selection. Complementary studies on laboratory rats will enable more detailed analysis of underlying mechanisms. To model the prenatal stress that programmes piglets, pregnant rats will be exposed to social defeat stress and both stress and pain responsiveness will be evaluated in the adult offspring. This will include, for stress, testing HPA axis responses to specific physical and emotional stressors, as well as measuring emotionality in a novel environment; measuring brain expression of CRH-related peptides, urocortins, and receptors which we considered important in stress responsivity. Pain sensitivity and gene expression patterns in the dorsal horn of the spinal cord will be compared with controls, especially considering proteins involved in NMDA receptor/complex-mediated synapses. As maternal HPA axis stress responses in pregnancy are naturally reduced by actions of neuroactive steroids (produced enzymatically in the brain from progesterone), the importance of this mechanism in protecting the fetuses will be tested by blocking synthesis (with finasteride) before stress to evaluate which offspring are more adversely affected. We will investigate whether neuroactive steroid (allopregnanolone) treatment reduces stress or pain responses of prenatally programmed rats. This will also be tested in pigs, to attempt to overwrite the adverse programming. These studies may identify selective targets that could potentially minimise early life adverse programming by means of either pharmacological/molecular or breeding plan intervention. Joint with BB/C/518965/1 and BB/C/518973/1.

Summary

unavailable

Committee	Closed Committee - Animal Sciences (AS)
Research Topics	Animal Health, Animal Welfare, Neuroscience and Behaviour, The 3 Rs (Replacement, Reduction and Refinement of animals in research)
Research Priority	X – Research Priority information not available
Research Initiative	Animal Welfare Programme (AWP) [2004]
Funding Scheme	X – not Funded via a specific Funding Scheme

Associated awards:

BB/C518965/1 Perinatal programming of stress response and nociceptive mechanisms and the welfare consequences

BB/C518973/1 Perinatal programming of stress response and nociceptive mechanisms and the welfare consequences

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